1. Field of the Invention
The present invention relates to new camptothecin derivatives useful as medicaments or intermediates therefor and a process for preparing the new camptothecin derivatives. More particularly, the present invention relates to new camptothecin derivatives carrying, in addition to a lower alkyl group in 7-position thereof, one or more substituents in 9-, 10-, 11- and/or 12-position thereof which are useful as anti-tumor drugs or intermediates therefor as well as a process for preparing the new camptothecin derivatives wherein 1,5-dioxo(5'-ethyl-2'H,5'H,6'H-6-oxopyrano) [3',4'-f]-.DELTA.6(8)tetrahydroindolidine is condensed with an o-acyl-aniline compound (or more specifically, a lower alkanophenone carrying an amino group in 2-position of its phenyl group and one or more substituents in 3-, 4-, 5- and/or 6-position thereof) and the resultant corresponding 20-deoxycamptothecin derivative is oxidized.
2. Description of the Prior Art
Camptothecin represented by the following structural formula: ##STR2## is an alkaloid extracted and isolated from Camptotheca accuminata (Nyssaceae), etc., which has a pentacyclic structure consisting of a characteristic fused 5-ring system consisting of quinoline (rings A and B), pyrroline (ring C), .alpha.-pyridone (ring D) and a six-membered lactone (ring E) and is distinguished by displaying a strong inhibitory activity toward biosynthesis of nucleic acid. In addition, camptothecin is a unique anti-tumor substance characterized by its rapid and reversible action, its lack of any cross-tolerance with the existing anti-tumor agents and by exhibiting a strong anti-tumor activity against experimentally transplanted carcinoma such as leukemia L-1210 in mice or Walker 256 tumor in rats. Although camptothecin is still regarded as one of the most potent substances possessing anti-tumor activity, the use of this compound itself for clinical treatments is significantly limited because of high toxicity. Moreover, camptothecin and the majority of derivatives thereof involve a problem of poor solubility in case of administration as medicaments.
For these reasons, a number of studies have been made heretofore not only to reduce toxicity of camptothecin while maintaining its anti-tumor activity by converting camptothecin chemically into its derivatives but also to make improvement in solubility of camptothecin and derivatives thereof by chemical modification of the camptothecin molecule or substituents therein. However, any chemical modification of the ring D and/or E of camptothecin, including ring-opening reactions of the ring D and/or E, revealed only failure in maintaining anti-tumor activity and very poor improvement in toxicity [J. Med. Chem., 19 (1976), 675]. From the chemotherapeutic point of view, therefore, it is of importance that the chemical modifications of camptothecin should be restricted in rings A, B and C without effecting any change in the rings D and E which are believed to be the essential structural elements for the expression of the above mentioned characteristic biological activities.
The present inventors made extensive researches for developing new class of camptothecin derivatives with co-workers on the basis of the above mentioned knowledge and found a process for preparing 5- and 7-substituted camptothecin derivatives (U.S. Pat. No. 4,399,282), a process for preparing various derivatives from these 5-and 7-substituted camptothecin derivatives (U.S. Pat. Nos. 4,399,276 and 4,399,282), a process for preparing 10- substituted camptothecin derivatives (U.S. Pat. Nos. 4,473,692 and 4,545,880), a process for preparing camptothecin derivatives disubstituted in 7-position and 9-, 10- or 11-position (U.S. Pat. No. 4,604,463) and a process for preparing 5- and/or 7-substituted camptothecin N-oxide derivatives (U.S. Pat. No. 4,513,138).
It was made clear from the studies on the various camptothecin derivatives prepared heretofore that introduction of an alkyl group into the 7-position of camptothecin tends to enhance anti-tumor activity. It is also noted that all of the camptothecin derivatives disclosed in these prior art references are derived from camptothecin or its derivatives but are not synthesized from other compounds which are not in possession of the fundamental structure of camptothecin.
For further extensive research based on these facts for sounding possibility of developing other new camptothecin derivatives also useful as anti-tumor agents or intermediates therefor and finding a new route for synthesizing camptothecin derivatives, there is still a great demand in the art for developing further new class of camptothecin derivatives carrying an alkyl group in 7-position thereof and various substituents in the ring A thereof according to a process quite different from the processes disclosed in the prior art references above mentioned.